CA2228036A1 - Use of prostane derivatives and the combination thereof with antibiotics in the treatment of bacterial infections - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
There is described the use of prostane derivatives of general formulae (I and Ia), wherein X1 is a -CH2-CH2, trans-CH=CH- or -CC- group, X2 is a linear or branched saturated hydrocarbon chain having from 1 to 6 carbon atoms, X3 is an -O- or -CH2- group, X4 is a -CH2- or -(CH2)3- group, X5 is a hydrogen atom or a -CC-R2 group, R1 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms or a phenyl group, R2 is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 carbon atoms, R3 is a hydrogen atom, an acyl radical having from 1 to 4 carbon atoms or a benzyl radical, and R4 is a hydrogen atom or a methyl group; the -O-R3- group being in the .alpha.- or .beta.-configuration, and their salts with physiologically tolerable bases when R1 represents a hydrogen atom, in the optional adjuvant treatment of bacterially induced meningitis, and also the combination of prostane derivatives with antibiotics.
Description
Use of prost~ne derivatives ~nd the combination thereof with antibiotics in the treatment of bacteri~l infections The invention relates to the use of prostane derivatives in the preparation of amedicament for the treatment of bacterially in~hlced meningitis and also to the combination of prostane derivatives with antibiotics.
Despite great advances in antimicrobial therapy, mortality in the case of bacterial meningitis is high (M.N. SCHWARTZ (1984) Bacterial meningitis: more involved than 0 just the meningitis. N. Engl. J. Med., 311: 912-914).
Pneumococci are aetiologically the most frequent causes of meningitis in adults and result in death in from 25% to 30% of cases. Clinical observations would suggest that an increase in the intracranial pressure (ICP), the formation of cerebral oedemas and cerebral vasculitis dete~nine the fatal course of the meningitis (H.-W. PFISTER (1989):
Complicated purulent meningitis of the adult: persisting high mortality caused by vasculitis and increased intracranial pressure, Nervenarzt, 60: 249-254). The inflammatory changes in bacterial meningitis are mediated by cytokines such as TNF.
TNF can be detected in humans with pneumococcal meningitis. (K.J. TRACEY (1994) Tumc r necrosis factor - alpha: In: The cytokine handbook A. THOMSON, eds.
Academic Press London, pp. 289-304, and also: T.P. LEIST et ai. (1988) Tumor necrosis factor alpha in cerebrospinal fluid during bacterial, but not viral, meningitis. Evaluation in murine model infectios and in patients. J. Exp. Med., 167 (5): 1743-1748). CSF
pleocytosis and cerebral oedema occur after the intracistemal increase in TNF (K.
SAUKKOMEN et ai. (1990) The role of cytokines in the eneration of infl~mm~tion and tissue damage in experimental gram positive meningitis. J. Exp. Med. 171 ( ): 439-448).
That points to a transmigration of leucocytes and a breakdown of the blood/brain barrier.
EP 0 011 591 desc~;ibes prostane derivatives and their preparation. Those prostane derivatives are compounds that are derived from prostacyclin (PGI.). They contain a methylene group instead of the 9-ether-oxygen atom in the prostacyclin. Prostanederivatives are used in the treatment of various diseases, the cardiovascular and thrombo-aggregation-inhibiting action being especially impc rtant.
The use of prostane derivatives as medicaments is known from EP 0 011 591. That 3s Application describes the lowering of peripheral, arteriai and coronary vascular resistance, the inhibition of thrombocyte aggregation and breaking down of platelet thrombi, myocardial cytoprotectic)n and therewith a lowering of the systemic blood pressure without at the same time reducing cardiac o utput and coronary blood supply;
SUBSTITUTE SHEET (RULE 26~
W O 97/06806 PCT~EP96/03481 treatment of stroke, prophylaxis and treatment of coronary heart diseases, coronary thrombosis, cardiac infarction, peripheral arterial ~ice~eC, arteriosclerosis and thrombosis, treatment of shock, inhibition of broncho-constriction, inhibition of gastric acid secretion and cytoprotection of the gastric mucous membrane and intestinal mucous S membrane; anti-aller~ic p,~.~el~ies, lowering of pulmonary, vascular resistance and of pulmonary blood plt;~.~.Ul~, promotion of renal blood flow, use instead of heparin or as an adjuvant in haemofiltration dialysis. storage of blood plasma stocks, ~ocpeci~lly of blood platelet stocks, inhibition of labour pains, treatment of toxaemia of pregnancy. anti-proliferative action and increase of cerebral blood flow.
EP 0 055 208, EP 0 099 538 and EP 0 119 949 describe carbacyclin derivatives that have similar indications to those of the at-ove-mentioned prostane derivatives.
EP 0 084 856 describes further prostane derivatives which have been proposed for use in 15 inhihiting thrombocyte aggregation. in lowering the systemic blood pressure or in the treatment of gastric ulcers, with beraprost being given special mention.
The use of prostane derivatives in the treatment of immune responses is described in various publications. For example, the treatment of anti-allergic properties is mentioned, 20 inter alia, in EP 0 011 591.
EP 0 055 208 describes, inter alia~ the anti-allergic action of carbacyclin derivatives.
The publication by H.J. GRUNDMANN et al. (199~) J. Infect. Dis. lt55: 1-5) describes in 25 detail the use of a prostane derivative, that is to say iloprost, in the treatment of septic shock.
DE 41 04 607 mentions the treatment of AIDS and diabetes with the aid of prostane derivatives.
The publication by K. SLIWA et al. (1991) Infection and Immunity, 59: 3846-3848)relates to the treatment of cerebral malaria with iloprost.
The object of the present invention is to use prostane derivatives for a further indication, 35 and also to combine prostane derivatives with antibiotics.
It has. surprisingly, been found that prostane derivatives of the general formulae I and la SUBSTITUTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 3 / \ C _ o _ ~1 X- \ C - C -,~1 s ~ formula I and ~b~ formul:lla y ~ X- -- 1 X
aH G-~ 3 OH ~-~
wherein Xl is a -CH.-CH~-, trans -CH=CH- or a -C~C- group, X~ is a linear or branched saturated hydrocarbon chain having from 1 to 6 carhon atoms, X3 iS an -O- or -CH,- group, S X~ is a -CH2 - or-(CH,)3- group, Xs is a hydrogen atom or a -C~C-R- group, R' is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having ~ or 6 carbon atoms or a phenyl group, R- is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 20 carbon atoms, R3 is a hydrogen atom, an acyl radical having from 1 to 4 carbon atoms or a benzyl radical, and R~ is a hydrogen atom or a methyl group;
the -o-R3- group being in the a- or ~-configuration, 25 and also salts thereof with physiologically tolerable bases when Rl represents a hydrogen atom, can be used (for the ~ ald~ion of a medicament) for the optional adjuvant treatment of bacterially induced meningitis.
Preference is given to the use according to the invention of the above-mentioned prostane 30 derivatives of the general formula I wherein Xl is a trans -CH=CH- group, X~ is a linear or branched saturated hydrocarbon chain having from 2 to 4 carbon atoms, X3isa-CH7- group, 35 X~ is a -CH,- group, Xs is a -C-C-R- group, Rl is a hydrogen atom, an alkyl grc up having ~rom 1 to 3 carbon atoms or a phenyl group, SUBSTITUTE SHEET (RULE 26) R- is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 3 carbon atoms, R3 is a hydrogen atom or an acyl radical having 2 carbon atoms, and R4 is a hydrogen atom;
5 the -o-R3- group being in the a- or ,~-configuration, and their salts with physiologically tolerable bases when Rl represents a hydrogen atom, (in the ~u~ d-~Lion of a medicament) for the optional adjuvant treatment of bacterially induced menin~ti~;
Especially preferred is the use according to the invention of the above-mentioned 10 prostane derivatives of the general formula I wherein X' is a trans -CH=CH- group, X- is a methylethylene group. the methyl group being bonded to the first carbc n atom of the ethylene group and the first carbon atom of the ethylene group facing the radical R~, 1~ X3is a-CH.- group, X4 is a-CH.- group, X5is a-C~C-R~ group, Rl is a hydrogen atom or a methyl group, R- is a methyl group or an ethyl group, 20 R3 is a hydrogen atom or a formyl group, and R4 is a hydrogen atom, the -o-R3- group being in the cl- or ,13-configuration, and their salts with physiologically tolerable bases when R~ represents a hydro_en atom.
(in the preparation of a medicament) for the optional adjuvant treatment of bacterially 25 i nduced meningitis.
Especially preferred is the use according to the invention of an above-mentioned prostane derivative of the general formula I wherein 30 X' is a trans -CH=CH- group, X- is a methvlethylene _roup, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom c f the ethylene group facing the radical R', X3iS a-CH,- group, 35 X~ is a -CH.- group, X5is a-C-C-R~ group, R' is a hydro_en atom, R- is a methyl group, S~JcsS 111 ~JTE SHEET ~RULE 26 S
R3 is a hydrogen atom, and R~ is a hydrogen atom, the -OH group being in the c~- or ,~-configuration, and its salts with physiologically tolerable bases, (in the preparation of a medicament) for the s optional adjuvant treatment of bacterially induced meningitis.
That compound has the name "iloprost" and has the systematic nomenclature 5-(E)-(lS,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]bicyclo[3.3.0]octen-3-ylidene-pentanoic acid. That is the most ~l~rell~,d compound 10 of the present invention.
A linear or branched saturated hydrocarbon chain having from 1 to 6 carbon atoms is understoc)d to be, for example, methylene~ ethylene, propylene or isopropylene. the methyl group being bonded to the first or second carbon atc m of the ethylene, counting 15 from the radical Rl; butylene, methylpropylene, ethylethylene or dimethylethylene, the methyl groups or ethyl groups heing bonded at any point on the alkylene chain; pentyl, methylbutylene, dimethylpropylene, ethylpropylene or methylethyl-ethylene, the methyl groups or ethyl groups being bonded at any point on the alkylene chain; hexylene, methylpentylene, dimethylbutylene or methylethylpropylene, the methyl group or ethyl 20 group being bonded at any point on the alkylene chain.
The alkyl group Rl includes straight-chained or branched alkyl groups having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl. butyl, isobutyl, tert-butyl, pentyl, neopentyl and hexyl The cycloalkyl group R1 may contain ~ or 6 carbon atoms in the ring.
The alkyl group R- may consist of a linear or branched, saturated or unsaturatedhydrocarbon chain having from 1 to 6 carbon atoms. Special mention may be made of the 30 methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, butenyl, isobutenyl, propenyl, pentenyl and hexenyl groups.
The acyl group R3 may consist of a straight-chained or branched-chain acyl group having from 1 to 4 carbon atoms, such as, for example. acetyl, propic)nyl, butyryl and isobutyryl.
Suitable for salt-formation with the free acids are inorganic and organic bases such as are known to the person skilled in the art for the formation of physiologically tolerable salts.
There may be mentic-ned bv way of example: alkali metal hvdrc xides, such as sodium and SUBSTITUTE SHEET (RULE 26) W O 97t06806 PCT/EP96/03481 potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide.ammonia, ~min.os, such as ethanolamine, diethanol~mine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)methylamine etc.. The ~-cyclodextrin clathrate formation is carried out as described in EP 0 259 468. All subject matter mentioned in that Patent Application is included by reference in the present Application.
Surprisingly, prostane derivatives are suitable for the treatment of encephalitis in bacterial menin~itis which occurs as a result of bacterial components after the bacteria have been destroyed by treatment with antibiotics. Hitherto, antibiotics (for example penicillins) in combination with glucocorticoids (d.oY~meth~cone) were used for the treatment (E.
TUOMANEN (1993) Bakterielle Meningitis und die Blut - Hirn - Schranke, Spektrum der Wissenschaft, 4: 86-90).
The present invention also relates to the use of the preferred compounds cicaprost.
eptaloprost, ciprosten and/or beraprost and their salts in the treatment of bacterially induced meningitis. The compounds including iloprost are listed in Table I with reference to their structure.
The present invention also relates to the use according to the invention of prostane derivatives together with physiologically toierable pharmacological excipients and carriers. Such substances are described in Remington's Pharmaceutic~ Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1989).
The methods of preparation for a number of the prostane derivatives that can be used according to the invention are described in detail in EP 0 011 591 or EP 0 084 856. The compounds of the general formulae I and la that are not expressly mentioned therein do not, however, differ in terins of the method of preparation. Their preparation lies within the general knowledge of a person skilled in the art.
The invention relates also to a combination of (i) prostane derivatives with (ii) antibiotics.
In that case, the prostane derivatives and the antibiotics may be administered at the same time or at different times by means of the same or different modes of administration.
Modes of administration are especially enteral, preferably oral, most preferably parenteral.
Suppositories, tablets, capsules. drops, injection solutions and suspensions are the appropriate forms for administration.
SUBSTITUTE SHEET (RULE 26) A combination of (i) prostane derivatives and (ii) antibiotics is preferred as a therapeutic agent. In that case, the prostane derivatives and the antibiotics may be ~1mini~tered at the same time or at different times by means of the same or different modes of administration.
Especially preferred is the use of a combination of (i) prostane derivatives and (ii) antibiotics in the treatment of bacterially inrlllced meningitis. In that case, the prostane derivatives and the antibiotics may be ~1mini~tered at the same time or at different times by means of the same or different modes of administration.
10 Antibiotics, their action and use are des.,~ ed in detail in Rompp Chemie-Lexikon, Jurgen FALBE and Man~red REGITZ (eds.), ninth edition, Stuttgart 1989, ISBN 3-13-734609-6, pages 206 to 208. The antibiotics described therein can be used in combination with the prostane derivatives of the general forrnulae I and Ia.
In the present study, changes in the regional cerebral blood flow (rCBF;), the intracranial pressure (ICP), cerebral oedema formation and in the number of cells in the cerebral fluid (CSF) are measured during the early phase of pneumococcus-in~luced meningitis in rats.
Those parameters for encephalitis and destruction of the blood/brain barrier are in~ ased after intracistemal injection of pneumococci in rats. They can be reduced in the presence 20 of the prostane derivatives according to the invention.
The prostane derivatives that can be used according to the invention demonstrate the action in the above-mentioned test at concentrations of from 1 to 500 ng per kg body weight and per minute.
The above-mentioned in vivo test system simulates the increased inflammation reaction resulting from antibiotic bacteriolysis and is therefore highly suitable for e~e,i.llental testing of adjuvant strategy therapies (H.W. PFISTER et ah (1992) Antioxidants attenuate microvascular changes in the early phase of experimental pneumococcal 30 meningitis in rats. Stroke, 23 (12): 1798-1804).
The compounds of the general formulae I and la are suitable for the optional adjuvant treatment of bacterially induced meningitis. A combination of compounds of the general formula I or la and of antibiotics is preferred. A combination of compounds of the general 35 formula I or la and antibiotics as a the.~lpeutic agent is advantageous. Also preferred is a use of a combination of cc mpounds of the general fc-rmula I c r la and of antibiotics in the treatment of bacterially induced meningitis.
SUBSTITUTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 For that therapeutic action, the suitable dose varies and depends, for example, on the colllpound of the general formulae I and la used, on the host, the mode of ~lmini~tration and the type and severity of the conditions that are to be treated. Generally, however, satisfactory results in ~nim~i~ are to be exrertecl at daily doses of from 1 to 30 !lg/kg s body weight. In larger m~mm~lc, for example hum~nc, a recommended dose is from 0.1 to 3 mg of the prostane derivatives of the general formulae I and la. Preferred values are from 0.3 to 1 mg per day, the administration generally lasting for to up to 4 days. The daily dose of prostane derivatives may be ~rlmini~tered advantageously in from 2 to 4 part doses per day. An antibiotic may be ~iminictered therewith.
The prostane derivatives of the general formulae I and la may be ~tlmini~tered in the case of systemic treatment by any customary route, especially enterally, preferably orally, most preferably parenterally. Suppositories, tablets, capsules. drops, injection solutions or suspensions are the a~ p~iate forms for administration.
The prostane derivative iloprost is the especially preferred compound. It is ~riminictered7 for example in larger m~mm~l~, for example hl-m~nc, in the above-mentioned manner.
The doses are in that case smaller than those indicated above by a factor of 2. An infusion solution in the form of a longer-term infusion preparation in a customary aqueous solvent, 20 for example physiological saline solution, is the preferred form of :l~minictration for systemic treatment. In that case, from 0.1 ng/kg/min to 100 nglkg/min, preferably from 1 to 10 ng/kg/min, are administered.
Therapeutic compositions can also be used that comprise a prostane derivative of the 2s general formula I or la to~ether with at least one pharmaceutical carrier, additive or diluent, all of which are physiologically tolerable. Such compositions can be prepared in a manner known ~se. Pharmacologically tolerable and suitable excipients and carriers are described, for example, in Remington s Pharm~reusical Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1980). The use of cyclodextrin clathrates, 30 which are described in European Patent Specification EP 0 259 468, is also possible.
ExamPle Meningitis is induced in anaesthetized adult male Wistar rats (from 250 to 350 g) by 35 intracisternal injection of 75 ~11 containing the equivalent of 1 x 107 cfiJ (colony forming units) of pneumococcal cell wall components. In the control animals, 75 ~l of physiological saline solution is injected into the cisterna ma~na (T.P. LEIST (1988) Tumor necrosis factor alpha in cerebrospinal fluid during bacterial, but not viral, SU.,;~ UTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 _g_ meningitis. Evaluation in murine model infections and in patients. J. Exp. Med. 167 (5):
1743-1748). In the third group, in addition to the intracisternal injection of pneumococci, iloprost is a~lminictered i.v. in a dose of 1 ~lg/h/kg.
The regional cerebral blood flow and the i.",~.c.~llial r~-es~,ure are determined 2, 4 and 6 s hours after the ineracranial injection of pneumococci and the technical procedure is descri'oed precisely in the following publications: H.-W. PFISTER et an (1990) J.
Cerebral Blood Flow and Metabolism, 10: 914-922, and also H.-W. PFISTER et ak (1992) Stroke, 23 (12): 1798-1804.
0 The Ixrcelllage content of cerebral fluid and the number of cells per ~ll of CSF are measured 6 hours after the injection of pneumococci, as described in H.-W. PFISTER et ah (1990) J. Cerebral Blood Flow and Metabolism, 10: 914-9Z''.
As can be seen from Tables 1 to 4, the prostane der.vatives used according to the 5 invention reduce significantly the pneumococcus-inrluce-l increase in cerebral blood flow, the intracranial blood pressure, the ~en_e.,Lage proportion of cerebral fluid and the number of cells per ~11 of CSF. The data are studied for significant differences with the aid of the Student-Newman-Keuls test (st~tistic package: SPSS for MS Windows Release6.1; Oneway, Analysis of Variance, significance level 0.05).
SU~S 11 l .JTE SHEET (RULE 26) _ Table I
Group/parameter LDF Oh LDF 2h LDF 4h LDF 6h 1. Control n=8 100 102_5 108+9 114+11 s Z. PCW n=8 100 150+30 208+40 252+48 3. Iloprost i.v. n=5 100 113+3 130+17 147+19 Table 2 o Group/parameter ICP Oh ICP 2h ICP 4h ICP 6h 1. Control n=8 3.2+1.7 3.9+1.5 3.9+1.63.6+1.4 2. PCW n=8 3.9+1.5 6.3_2.2 8.9+3.510.9+3.6 3. Iloprost i.v. n=4 3.2+1.3 4.2+1.84.2+1.2 4.6 ~ 1.1 Ts~ble 3 Grouplparameter Cells/~ll CSF OhCellsl~ll CSF 6h 1. Control n=8 4_3 6+6 2. PCW n=7/6 5+3 2287+978 3. Iloprost i.v. n=5 4~3 518+190 T~ble 4 Group/parameter Cerebral fluid in %
1. Control n=8 78.50+0.55 2. PCW n=8 79.89+0.51 3. Iloprost i.v. n=5 78.55+0.15 30 Legend:
LDF = Laser/Doppler/Flow (regional cerebral blood flow) ICP = intracranial pressure PCW = pneumococcal cell wall components aa) Control: NaCI i.c.
bb) PCW: PCW i.c. equivalent of 1 x 107 CFU Strept. pneum. - untreated meningitis.
cc) Iloprost i.v.: PCW i.c. and iloprost continuously i.v. 1 ~lg/h/kg SUBSTITUTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 Blood gases, mean ~ u~e of final expiratory CO~ within the normal range;
.Anzl~sth~osia: pentobarbital 100 mg/kg.
S~ JTE SHEET (RULE 26)
Despite great advances in antimicrobial therapy, mortality in the case of bacterial meningitis is high (M.N. SCHWARTZ (1984) Bacterial meningitis: more involved than 0 just the meningitis. N. Engl. J. Med., 311: 912-914).
Pneumococci are aetiologically the most frequent causes of meningitis in adults and result in death in from 25% to 30% of cases. Clinical observations would suggest that an increase in the intracranial pressure (ICP), the formation of cerebral oedemas and cerebral vasculitis dete~nine the fatal course of the meningitis (H.-W. PFISTER (1989):
Complicated purulent meningitis of the adult: persisting high mortality caused by vasculitis and increased intracranial pressure, Nervenarzt, 60: 249-254). The inflammatory changes in bacterial meningitis are mediated by cytokines such as TNF.
TNF can be detected in humans with pneumococcal meningitis. (K.J. TRACEY (1994) Tumc r necrosis factor - alpha: In: The cytokine handbook A. THOMSON, eds.
Academic Press London, pp. 289-304, and also: T.P. LEIST et ai. (1988) Tumor necrosis factor alpha in cerebrospinal fluid during bacterial, but not viral, meningitis. Evaluation in murine model infectios and in patients. J. Exp. Med., 167 (5): 1743-1748). CSF
pleocytosis and cerebral oedema occur after the intracistemal increase in TNF (K.
SAUKKOMEN et ai. (1990) The role of cytokines in the eneration of infl~mm~tion and tissue damage in experimental gram positive meningitis. J. Exp. Med. 171 ( ): 439-448).
That points to a transmigration of leucocytes and a breakdown of the blood/brain barrier.
EP 0 011 591 desc~;ibes prostane derivatives and their preparation. Those prostane derivatives are compounds that are derived from prostacyclin (PGI.). They contain a methylene group instead of the 9-ether-oxygen atom in the prostacyclin. Prostanederivatives are used in the treatment of various diseases, the cardiovascular and thrombo-aggregation-inhibiting action being especially impc rtant.
The use of prostane derivatives as medicaments is known from EP 0 011 591. That 3s Application describes the lowering of peripheral, arteriai and coronary vascular resistance, the inhibition of thrombocyte aggregation and breaking down of platelet thrombi, myocardial cytoprotectic)n and therewith a lowering of the systemic blood pressure without at the same time reducing cardiac o utput and coronary blood supply;
SUBSTITUTE SHEET (RULE 26~
W O 97/06806 PCT~EP96/03481 treatment of stroke, prophylaxis and treatment of coronary heart diseases, coronary thrombosis, cardiac infarction, peripheral arterial ~ice~eC, arteriosclerosis and thrombosis, treatment of shock, inhibition of broncho-constriction, inhibition of gastric acid secretion and cytoprotection of the gastric mucous membrane and intestinal mucous S membrane; anti-aller~ic p,~.~el~ies, lowering of pulmonary, vascular resistance and of pulmonary blood plt;~.~.Ul~, promotion of renal blood flow, use instead of heparin or as an adjuvant in haemofiltration dialysis. storage of blood plasma stocks, ~ocpeci~lly of blood platelet stocks, inhibition of labour pains, treatment of toxaemia of pregnancy. anti-proliferative action and increase of cerebral blood flow.
EP 0 055 208, EP 0 099 538 and EP 0 119 949 describe carbacyclin derivatives that have similar indications to those of the at-ove-mentioned prostane derivatives.
EP 0 084 856 describes further prostane derivatives which have been proposed for use in 15 inhihiting thrombocyte aggregation. in lowering the systemic blood pressure or in the treatment of gastric ulcers, with beraprost being given special mention.
The use of prostane derivatives in the treatment of immune responses is described in various publications. For example, the treatment of anti-allergic properties is mentioned, 20 inter alia, in EP 0 011 591.
EP 0 055 208 describes, inter alia~ the anti-allergic action of carbacyclin derivatives.
The publication by H.J. GRUNDMANN et al. (199~) J. Infect. Dis. lt55: 1-5) describes in 25 detail the use of a prostane derivative, that is to say iloprost, in the treatment of septic shock.
DE 41 04 607 mentions the treatment of AIDS and diabetes with the aid of prostane derivatives.
The publication by K. SLIWA et al. (1991) Infection and Immunity, 59: 3846-3848)relates to the treatment of cerebral malaria with iloprost.
The object of the present invention is to use prostane derivatives for a further indication, 35 and also to combine prostane derivatives with antibiotics.
It has. surprisingly, been found that prostane derivatives of the general formulae I and la SUBSTITUTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 3 / \ C _ o _ ~1 X- \ C - C -,~1 s ~ formula I and ~b~ formul:lla y ~ X- -- 1 X
aH G-~ 3 OH ~-~
wherein Xl is a -CH.-CH~-, trans -CH=CH- or a -C~C- group, X~ is a linear or branched saturated hydrocarbon chain having from 1 to 6 carhon atoms, X3 iS an -O- or -CH,- group, S X~ is a -CH2 - or-(CH,)3- group, Xs is a hydrogen atom or a -C~C-R- group, R' is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having ~ or 6 carbon atoms or a phenyl group, R- is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 20 carbon atoms, R3 is a hydrogen atom, an acyl radical having from 1 to 4 carbon atoms or a benzyl radical, and R~ is a hydrogen atom or a methyl group;
the -o-R3- group being in the a- or ~-configuration, 25 and also salts thereof with physiologically tolerable bases when Rl represents a hydrogen atom, can be used (for the ~ ald~ion of a medicament) for the optional adjuvant treatment of bacterially induced meningitis.
Preference is given to the use according to the invention of the above-mentioned prostane 30 derivatives of the general formula I wherein Xl is a trans -CH=CH- group, X~ is a linear or branched saturated hydrocarbon chain having from 2 to 4 carbon atoms, X3isa-CH7- group, 35 X~ is a -CH,- group, Xs is a -C-C-R- group, Rl is a hydrogen atom, an alkyl grc up having ~rom 1 to 3 carbon atoms or a phenyl group, SUBSTITUTE SHEET (RULE 26) R- is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 3 carbon atoms, R3 is a hydrogen atom or an acyl radical having 2 carbon atoms, and R4 is a hydrogen atom;
5 the -o-R3- group being in the a- or ,~-configuration, and their salts with physiologically tolerable bases when Rl represents a hydrogen atom, (in the ~u~ d-~Lion of a medicament) for the optional adjuvant treatment of bacterially induced menin~ti~;
Especially preferred is the use according to the invention of the above-mentioned 10 prostane derivatives of the general formula I wherein X' is a trans -CH=CH- group, X- is a methylethylene group. the methyl group being bonded to the first carbc n atom of the ethylene group and the first carbon atom of the ethylene group facing the radical R~, 1~ X3is a-CH.- group, X4 is a-CH.- group, X5is a-C~C-R~ group, Rl is a hydrogen atom or a methyl group, R- is a methyl group or an ethyl group, 20 R3 is a hydrogen atom or a formyl group, and R4 is a hydrogen atom, the -o-R3- group being in the cl- or ,13-configuration, and their salts with physiologically tolerable bases when R~ represents a hydro_en atom.
(in the preparation of a medicament) for the optional adjuvant treatment of bacterially 25 i nduced meningitis.
Especially preferred is the use according to the invention of an above-mentioned prostane derivative of the general formula I wherein 30 X' is a trans -CH=CH- group, X- is a methvlethylene _roup, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom c f the ethylene group facing the radical R', X3iS a-CH,- group, 35 X~ is a -CH.- group, X5is a-C-C-R~ group, R' is a hydro_en atom, R- is a methyl group, S~JcsS 111 ~JTE SHEET ~RULE 26 S
R3 is a hydrogen atom, and R~ is a hydrogen atom, the -OH group being in the c~- or ,~-configuration, and its salts with physiologically tolerable bases, (in the preparation of a medicament) for the s optional adjuvant treatment of bacterially induced meningitis.
That compound has the name "iloprost" and has the systematic nomenclature 5-(E)-(lS,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]bicyclo[3.3.0]octen-3-ylidene-pentanoic acid. That is the most ~l~rell~,d compound 10 of the present invention.
A linear or branched saturated hydrocarbon chain having from 1 to 6 carbon atoms is understoc)d to be, for example, methylene~ ethylene, propylene or isopropylene. the methyl group being bonded to the first or second carbon atc m of the ethylene, counting 15 from the radical Rl; butylene, methylpropylene, ethylethylene or dimethylethylene, the methyl groups or ethyl groups heing bonded at any point on the alkylene chain; pentyl, methylbutylene, dimethylpropylene, ethylpropylene or methylethyl-ethylene, the methyl groups or ethyl groups being bonded at any point on the alkylene chain; hexylene, methylpentylene, dimethylbutylene or methylethylpropylene, the methyl group or ethyl 20 group being bonded at any point on the alkylene chain.
The alkyl group Rl includes straight-chained or branched alkyl groups having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl. butyl, isobutyl, tert-butyl, pentyl, neopentyl and hexyl The cycloalkyl group R1 may contain ~ or 6 carbon atoms in the ring.
The alkyl group R- may consist of a linear or branched, saturated or unsaturatedhydrocarbon chain having from 1 to 6 carbon atoms. Special mention may be made of the 30 methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, butenyl, isobutenyl, propenyl, pentenyl and hexenyl groups.
The acyl group R3 may consist of a straight-chained or branched-chain acyl group having from 1 to 4 carbon atoms, such as, for example. acetyl, propic)nyl, butyryl and isobutyryl.
Suitable for salt-formation with the free acids are inorganic and organic bases such as are known to the person skilled in the art for the formation of physiologically tolerable salts.
There may be mentic-ned bv way of example: alkali metal hvdrc xides, such as sodium and SUBSTITUTE SHEET (RULE 26) W O 97t06806 PCT/EP96/03481 potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide.ammonia, ~min.os, such as ethanolamine, diethanol~mine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)methylamine etc.. The ~-cyclodextrin clathrate formation is carried out as described in EP 0 259 468. All subject matter mentioned in that Patent Application is included by reference in the present Application.
Surprisingly, prostane derivatives are suitable for the treatment of encephalitis in bacterial menin~itis which occurs as a result of bacterial components after the bacteria have been destroyed by treatment with antibiotics. Hitherto, antibiotics (for example penicillins) in combination with glucocorticoids (d.oY~meth~cone) were used for the treatment (E.
TUOMANEN (1993) Bakterielle Meningitis und die Blut - Hirn - Schranke, Spektrum der Wissenschaft, 4: 86-90).
The present invention also relates to the use of the preferred compounds cicaprost.
eptaloprost, ciprosten and/or beraprost and their salts in the treatment of bacterially induced meningitis. The compounds including iloprost are listed in Table I with reference to their structure.
The present invention also relates to the use according to the invention of prostane derivatives together with physiologically toierable pharmacological excipients and carriers. Such substances are described in Remington's Pharmaceutic~ Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1989).
The methods of preparation for a number of the prostane derivatives that can be used according to the invention are described in detail in EP 0 011 591 or EP 0 084 856. The compounds of the general formulae I and la that are not expressly mentioned therein do not, however, differ in terins of the method of preparation. Their preparation lies within the general knowledge of a person skilled in the art.
The invention relates also to a combination of (i) prostane derivatives with (ii) antibiotics.
In that case, the prostane derivatives and the antibiotics may be administered at the same time or at different times by means of the same or different modes of administration.
Modes of administration are especially enteral, preferably oral, most preferably parenteral.
Suppositories, tablets, capsules. drops, injection solutions and suspensions are the appropriate forms for administration.
SUBSTITUTE SHEET (RULE 26) A combination of (i) prostane derivatives and (ii) antibiotics is preferred as a therapeutic agent. In that case, the prostane derivatives and the antibiotics may be ~1mini~tered at the same time or at different times by means of the same or different modes of administration.
Especially preferred is the use of a combination of (i) prostane derivatives and (ii) antibiotics in the treatment of bacterially inrlllced meningitis. In that case, the prostane derivatives and the antibiotics may be ~1mini~tered at the same time or at different times by means of the same or different modes of administration.
10 Antibiotics, their action and use are des.,~ ed in detail in Rompp Chemie-Lexikon, Jurgen FALBE and Man~red REGITZ (eds.), ninth edition, Stuttgart 1989, ISBN 3-13-734609-6, pages 206 to 208. The antibiotics described therein can be used in combination with the prostane derivatives of the general forrnulae I and Ia.
In the present study, changes in the regional cerebral blood flow (rCBF;), the intracranial pressure (ICP), cerebral oedema formation and in the number of cells in the cerebral fluid (CSF) are measured during the early phase of pneumococcus-in~luced meningitis in rats.
Those parameters for encephalitis and destruction of the blood/brain barrier are in~ ased after intracistemal injection of pneumococci in rats. They can be reduced in the presence 20 of the prostane derivatives according to the invention.
The prostane derivatives that can be used according to the invention demonstrate the action in the above-mentioned test at concentrations of from 1 to 500 ng per kg body weight and per minute.
The above-mentioned in vivo test system simulates the increased inflammation reaction resulting from antibiotic bacteriolysis and is therefore highly suitable for e~e,i.llental testing of adjuvant strategy therapies (H.W. PFISTER et ah (1992) Antioxidants attenuate microvascular changes in the early phase of experimental pneumococcal 30 meningitis in rats. Stroke, 23 (12): 1798-1804).
The compounds of the general formulae I and la are suitable for the optional adjuvant treatment of bacterially induced meningitis. A combination of compounds of the general formula I or la and of antibiotics is preferred. A combination of compounds of the general 35 formula I or la and antibiotics as a the.~lpeutic agent is advantageous. Also preferred is a use of a combination of cc mpounds of the general fc-rmula I c r la and of antibiotics in the treatment of bacterially induced meningitis.
SUBSTITUTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 For that therapeutic action, the suitable dose varies and depends, for example, on the colllpound of the general formulae I and la used, on the host, the mode of ~lmini~tration and the type and severity of the conditions that are to be treated. Generally, however, satisfactory results in ~nim~i~ are to be exrertecl at daily doses of from 1 to 30 !lg/kg s body weight. In larger m~mm~lc, for example hum~nc, a recommended dose is from 0.1 to 3 mg of the prostane derivatives of the general formulae I and la. Preferred values are from 0.3 to 1 mg per day, the administration generally lasting for to up to 4 days. The daily dose of prostane derivatives may be ~rlmini~tered advantageously in from 2 to 4 part doses per day. An antibiotic may be ~iminictered therewith.
The prostane derivatives of the general formulae I and la may be ~tlmini~tered in the case of systemic treatment by any customary route, especially enterally, preferably orally, most preferably parenterally. Suppositories, tablets, capsules. drops, injection solutions or suspensions are the a~ p~iate forms for administration.
The prostane derivative iloprost is the especially preferred compound. It is ~riminictered7 for example in larger m~mm~l~, for example hl-m~nc, in the above-mentioned manner.
The doses are in that case smaller than those indicated above by a factor of 2. An infusion solution in the form of a longer-term infusion preparation in a customary aqueous solvent, 20 for example physiological saline solution, is the preferred form of :l~minictration for systemic treatment. In that case, from 0.1 ng/kg/min to 100 nglkg/min, preferably from 1 to 10 ng/kg/min, are administered.
Therapeutic compositions can also be used that comprise a prostane derivative of the 2s general formula I or la to~ether with at least one pharmaceutical carrier, additive or diluent, all of which are physiologically tolerable. Such compositions can be prepared in a manner known ~se. Pharmacologically tolerable and suitable excipients and carriers are described, for example, in Remington s Pharm~reusical Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1980). The use of cyclodextrin clathrates, 30 which are described in European Patent Specification EP 0 259 468, is also possible.
ExamPle Meningitis is induced in anaesthetized adult male Wistar rats (from 250 to 350 g) by 35 intracisternal injection of 75 ~11 containing the equivalent of 1 x 107 cfiJ (colony forming units) of pneumococcal cell wall components. In the control animals, 75 ~l of physiological saline solution is injected into the cisterna ma~na (T.P. LEIST (1988) Tumor necrosis factor alpha in cerebrospinal fluid during bacterial, but not viral, SU.,;~ UTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 _g_ meningitis. Evaluation in murine model infections and in patients. J. Exp. Med. 167 (5):
1743-1748). In the third group, in addition to the intracisternal injection of pneumococci, iloprost is a~lminictered i.v. in a dose of 1 ~lg/h/kg.
The regional cerebral blood flow and the i.",~.c.~llial r~-es~,ure are determined 2, 4 and 6 s hours after the ineracranial injection of pneumococci and the technical procedure is descri'oed precisely in the following publications: H.-W. PFISTER et an (1990) J.
Cerebral Blood Flow and Metabolism, 10: 914-922, and also H.-W. PFISTER et ak (1992) Stroke, 23 (12): 1798-1804.
0 The Ixrcelllage content of cerebral fluid and the number of cells per ~ll of CSF are measured 6 hours after the injection of pneumococci, as described in H.-W. PFISTER et ah (1990) J. Cerebral Blood Flow and Metabolism, 10: 914-9Z''.
As can be seen from Tables 1 to 4, the prostane der.vatives used according to the 5 invention reduce significantly the pneumococcus-inrluce-l increase in cerebral blood flow, the intracranial blood pressure, the ~en_e.,Lage proportion of cerebral fluid and the number of cells per ~11 of CSF. The data are studied for significant differences with the aid of the Student-Newman-Keuls test (st~tistic package: SPSS for MS Windows Release6.1; Oneway, Analysis of Variance, significance level 0.05).
SU~S 11 l .JTE SHEET (RULE 26) _ Table I
Group/parameter LDF Oh LDF 2h LDF 4h LDF 6h 1. Control n=8 100 102_5 108+9 114+11 s Z. PCW n=8 100 150+30 208+40 252+48 3. Iloprost i.v. n=5 100 113+3 130+17 147+19 Table 2 o Group/parameter ICP Oh ICP 2h ICP 4h ICP 6h 1. Control n=8 3.2+1.7 3.9+1.5 3.9+1.63.6+1.4 2. PCW n=8 3.9+1.5 6.3_2.2 8.9+3.510.9+3.6 3. Iloprost i.v. n=4 3.2+1.3 4.2+1.84.2+1.2 4.6 ~ 1.1 Ts~ble 3 Grouplparameter Cells/~ll CSF OhCellsl~ll CSF 6h 1. Control n=8 4_3 6+6 2. PCW n=7/6 5+3 2287+978 3. Iloprost i.v. n=5 4~3 518+190 T~ble 4 Group/parameter Cerebral fluid in %
1. Control n=8 78.50+0.55 2. PCW n=8 79.89+0.51 3. Iloprost i.v. n=5 78.55+0.15 30 Legend:
LDF = Laser/Doppler/Flow (regional cerebral blood flow) ICP = intracranial pressure PCW = pneumococcal cell wall components aa) Control: NaCI i.c.
bb) PCW: PCW i.c. equivalent of 1 x 107 CFU Strept. pneum. - untreated meningitis.
cc) Iloprost i.v.: PCW i.c. and iloprost continuously i.v. 1 ~lg/h/kg SUBSTITUTE SHEET (RULE 26) W O 97/06806 PCT~EP96/03481 Blood gases, mean ~ u~e of final expiratory CO~ within the normal range;
.Anzl~sth~osia: pentobarbital 100 mg/kg.
S~ JTE SHEET (RULE 26)
Claims (10)
1. Use of prostane derivatives of the general formulae I and Ia and wherein X1 is a -CH2-CH2-, trans -CH=CH- or -C~C- group, X2 is a linear or branched saturated hydrocarbon chain having from 1 to 6 carbonatoms, X3 is an -O- or -CH2- group, X4 is a -CH2- or -(CH2)3- group, X5 is a hydrogen atom or a -C~C-R2 group, R1 is a hydrogen atom. an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms or a phenyl group, R2 is a linear or branched, saturated or unsaturated hydrocarbon chain having from 1 to 6 carbon atoms, R3 is a hydrogen atom, an acyl radical having from 1 to 4 carbon atoms or a benzyl radical, and R4 is a hydrogen atom or a methyl group;
the -O-R3- group being in the .alpha.- or .beta.-configuration, and their salts. with physiologically tolerable bases when R1 represents a hydrogen atom, for the preparation of a medicament for the treatment of bacterially induced meningitis.
the -O-R3- group being in the .alpha.- or .beta.-configuration, and their salts. with physiologically tolerable bases when R1 represents a hydrogen atom, for the preparation of a medicament for the treatment of bacterially induced meningitis.
2. Use of prostane derivatives according to claim 1, which in one composition comprises .beta.-cyclodextrin clathrate.
3. Use of prostane derivatives of the general formula I, according to any one ofthe preceding claims, wherein X1 is a trans -CH=CH- group, X2 is a linear or branched saturated hydrocarbon chain having from 2 to 4 carbonatoms, X3 is a -CH2- group, X4 is a -CH2- group, X5 is a -C~C-R2- group, R1 is a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or a phenyl group, R2 is a linear or branched. saturated or unsaturated hydrocarbon chain having from 1 to 3 carbon atoms, R3 is a hydrogen atom or an acyl radical having 2 carbon atoms, and R4 is a hydrogen atom;
the -O-R3- group being in the .alpha. or .beta.-configuration, and their salts with physiologically tolerable bases when R1 represents a hydrogen atom, for the preparation of a medicament for the treatment of bacterially induced meningitis.
the -O-R3- group being in the .alpha. or .beta.-configuration, and their salts with physiologically tolerable bases when R1 represents a hydrogen atom, for the preparation of a medicament for the treatment of bacterially induced meningitis.
4. Use of prostane derivatives of the general formula I, according to claim 3, wherein X1 is a trans -CH=CH- group, X2 is a methylethylene group, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom of the ethylene group facing the radical R1, X3 is a -CH2- group, X4 is a -CH2- group, X5 is a -C~C-R2 group R1 is a hydrogen atom or a methyl group.
R2 is a methyl group or an ethyl group, R3 is a hydrogen atom or a formyl group, and R4 is a hydrogen atom, the -O-R3- group being in the .alpha.- or .beta.-configuration, and their salts with physiologically tolerable bases when R1 represents a hydrogen atom, for the preparation of a medicament for the treatment of bacterially induced meningitis.
R2 is a methyl group or an ethyl group, R3 is a hydrogen atom or a formyl group, and R4 is a hydrogen atom, the -O-R3- group being in the .alpha.- or .beta.-configuration, and their salts with physiologically tolerable bases when R1 represents a hydrogen atom, for the preparation of a medicament for the treatment of bacterially induced meningitis.
5. Use of a prostane derivative of the general formula I, according to claim 4, wherein X1 is a trans -CH=CH- group, X2 is a metnylethylene group, the methyl group being bonded to the first carbon atom of the ethylene group and the first carbon atom of the ethylene group facing the radical R1, X3 is a-CH2- group.
X4 is a -CH2- group, X5 is a -C~C-R2 group, R1 is a hydrogen atom, R2 is a methyl group, R3 is a hydrogen atom, and R4 is a hydrogen atom, the -OH group being in the .alpha.- or .beta.-configuration, and its salts with physiologically tolerable bases, for the preparation of a medicament for the treatment of bacterially induced meningitis.
X4 is a -CH2- group, X5 is a -C~C-R2 group, R1 is a hydrogen atom, R2 is a methyl group, R3 is a hydrogen atom, and R4 is a hydrogen atom, the -OH group being in the .alpha.- or .beta.-configuration, and its salts with physiologically tolerable bases, for the preparation of a medicament for the treatment of bacterially induced meningitis.
6. Use of prostane derivatives according to claim 1, characterised in that the prostane derivatives are cicaprost, eptaloprost, ciprosten and/or beraprost and their salts, for the preparation of a medicament for the treatment of bacterially induced meningitis.
7. Use of prostane derivatives according to at least one of the preceding claims, together with physiologically tolerable pharmacologoical excipients and carriers.
8. Combination of (i) prostane derivatives according to any one of the precedingclaims with (ii) antiobiotics.
9. Combination of (i) prostane derivatives according to any one of the precedingclaims with antibiotics, as a therapeutic agent.
10. Use of a combination of (i) prostane derivatives and (ii) antiobiotics, according to claims 8 and 9, for the preparation of a medicament for the treatment of bacterially induced meningitis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19530884.0 | 1995-08-11 | ||
| DE19530884A DE19530884C2 (en) | 1995-08-11 | 1995-08-11 | Use of prostane derivatives and their combination with antibiotics for the treatment of bacterial meningitis |
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| EP (1) | EP0852497B1 (en) |
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| WO2008058766A1 (en) * | 2006-11-16 | 2008-05-22 | Bayer Schering Pharma Aktiengesellschaft | Ep2 and ep4 agonists as agents for the treatment of influenza a viral infection |
| EP2803365A1 (en) | 2013-05-14 | 2014-11-19 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | Use of clonazepam in combination with antibiotic in the treatment of bacterially induced meningitis |
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| JPS58124778A (en) * | 1982-01-20 | 1983-07-25 | Toray Ind Inc | 5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivative |
| US4665088A (en) * | 1984-11-14 | 1987-05-12 | The Research Foundation Of State University Of New York | (E-Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxides |
| FI870658A (en) * | 1986-02-18 | 1987-08-19 | Syntex Inc | INFEKTIONSHINDRANDE INJICERBARA PRODUKTER. |
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